Throughout this application, various publications are referenced within the text. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
When less uric acid is excreted than is produced, plasma urate concentration (pUAc) rises and may exceed the limit of solubility (˜7 mg/dL or 0.42 mM), causing the deposition of monosodium urate (MSU) in tissues. In susceptible individuals intra-articular MSU crystals trigger inflammatory attacks of gout (Becker M A: Hyperuricemia and gout. In: The Metabolic and Molecular Bases of Inherited Disease. Edited by Scriver C R, Beaudet A L, Sly W S, Valle D, 8th edn. New York: McGraw-Hill; 2001: 2513-2535; Terkeltaub R A: Clinical practice. Gout. N Engl J Med 2003, 349(17):1647-1655; and Wortmann R L et al.: Gout and Hyperuricemia. In: Kelley's Textbook of Rheumatology. Edited by Ruddy S, Harris E D, Jr., Sledge C B, 6th edn. St. Louis: W. B. Saunders; 2001: 1339-1371).
Blocking urate production by inhibiting xanthine oxidase, or promoting renal urate excretion, can prevent further MSU crystal accumulation in tissues if plasma urate concentration is maintained below 6 mg/dL (Li-Yu J et al. J Rheumatol 2001, 28(3):577-580; Perez-Ruiz F, et al. Arthritis Rheum 2002, 47(4):356-360; and Shoji A, et al. Arthritis Rheum 2004, 51(3):321-325). If hyperuricemia is poorly controlled, gout may become chronic, leading to arthropathy, nephropathy, and various complications of tophi. Conventional therapy may be less effective at this stage since expanded tissue stores may only slowly be depleted by blocking new urate production, particularly if urate excretion is impaired by renal insufficiency, or by concomitant therapy with diuretics or cyclosporine.
Most mammals can convert uric acid to the more soluble compound allantoin. This metabolic route of elimination is inoperative in humans owing to mutation of the urate oxidase (uricase) gene during evolution. Parenteral uricase derived from Aspergillus flavus (Rasburicase, Sanofi Synthelabo) is effective in preventing acute uric acid nephropathy in patients with malignancies (Coiffier B. et al. J Clin Oncol 2003, 21(23):4402-4406; and Goldman S C, et al. Blood 2001, 97(10):2998-3003). This and other uricase preparations have been used with apparent benefit to treat small numbers of patients with refractory gout (Kissel P. et al. Nature 1968, 217:72-74; London M, et al. Science 1957, 125:937-938; Montagnac R. et al. Nephrologie 1990, 11(4):259; Moolenburgh J D, et al. Clin Rheumatol 2005:1-4; Mourad G. et al. Presse Med 1984, 13(42):2585; and Richette P, et al. Nature Clinical Practice Rheumatology 2006, 2(6):338-342). However, no clinical trials for this indication have been reported, and a relatively short circulating life and potential immunogenicity have limited their wider application for treating gout.
Attaching the inert polymer polyethylene glycol (PEG) to proteins can extend their circulating life and diminish immune recognition (Abuchowski A, et al. J Biol Chem 1977, 252(11):3582-3586; Harris J M, et al. Nat Rev Drug Discov 2003, 2(3):214-221; Veronese F M, et al. Adv Drug Deliv Rev 2002, 54(4):453-456. The development of a PEGylated recombinant mammalian uricase for treating gout is being pursued (Kelly S J, et al. J Am Soc Nephrol 2001, 12:1001-1009). In an initial Phase I clinical trial, 13 subjects with severe gout and mean pUAc >11 mg/dL received single subcutaneous (SC) injections of 4 to 24 mg of PEG-uricase (Ganson N J, et al. Arthritis Res Ther 2005, 8(1):R12). Within 7 days, pUAc fell by a mean of ˜8 mg/dL, and normalized in 11 subjects. At doses of 8-24 mg, mean pUAc remained <6 mg/dL at 21 days post-injection. Although very effective, SC-injected PEG-uricase caused transient local pain and was slowly absorbed. It was also rapidly cleared in 5 subjects who developed antibodies that, unexpectedly, reacted with PEG rather than with the uricase protein. Three of the latter subjects had allergic reactions that began at the injection site at 8-9 days post-injection (Ganson N J, et al. Arthritis Res Ther 2005, 8(1):R12).